An important source of individual variability in brain function is genetic variability in dopamine (DA) regulation. Extracellular DA levels are regulated by clearance mechanisms such as COMT (catechol-O- methyltransferase), an enzyme that degrades DA in synapses. COMT has two genetic variants which produce different levels of DA in prefrontal cortex. Effects of this gene have been observed in functional activation during working memory. However, it is currently unknown whether those genetic effects extend to deactivation and functional connectivity. During performance of working memory tasks, activity within certain "task- negative" regions is suppressed compared to task-free conditions. Activity within these regions is temporally correlated during task and during rest, suggesting that they form a network. It is possible that COMT genotype modulates activation in task-relevant regions, as well as deactivation and functional connectivity of task- negative regions. Here, healthy adults carrying variants of COMT will undergo fMRI during a working memory task with load manipulation and during rest. Specific Aim 1 will characterize differences by COMT alleles and by working memory load in activated and deactivated regions. ANOVAs examining COMT and WM load effects on activation will localize independent (main effect of COMT) and interactive (COMT X WM load) effects of the genotype. Specific Aim 2 will characterize differences by COMT alleles and by working memory load in functional connectivity during working memory. Activity within observed task-positive and task-negative regions will be correlated to determine within-network functional connectivities. Subsequently, ANOVAs examining COMT and WM load effects on connectivity will be conducted. Specific Aim 3 will examine differences in resting-state functional connectivity by COMT alleles. Independent Components Analysis will be used to delineate each subject's task-negative network. A group analysis will then be conducted examining the effect of COMT on the network's spatial extent. Findings of the proposed study will extend current knowledge of COMT effects (activation during task-states) and will also break new ground (deactivation and connectivity during task-states and resting-state). Importantly, the integrity of the task-negative network predicts healthy attentional control and is disrupted in Schizophrenia, a disorder with working memory dysfunction whose pathogenesis involves COMT. PUBLIC HEALTH RELEVANCE: This proposal will investigate how COMT, a gene which regulates dopamine, may influence brain activity and communication between brain regions during a memory task. This research may increase understanding of schizophrenia, which is linked to COMT and associated with memory problems.